Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia

David G Francis, Volodymyr Rybalchenko, Arie Struyk, Stephen C Cannon
Neurology 2011 May 10, 76 (19): 1635-41

BACKGROUND: Hypokalemic periodic paralysis (HypoPP) is associated with mutations in either the Ca(V)1.1 calcium channel or the Na(V)1.4 sodium channel. Some Na(V)1.4 HypoPP mutations have been shown to cause an anomalous inward current that may contribute to the attacks of paralysis. Herein, we test whether disease-associated Na(V)1.4 mutations in previously untested homologous regions of the channel also give rise to the anomalous current.

METHODS: The functional properties of mutant Na(V)1.4 channels were studied with voltage-clamp techniques in an oocyte expression system.

RESULTS: The HypoPP mutation Na(V)1.4-R1132Q conducts an anomalous gating pore current, but the homologous R1448C mutation in paramyotonia congenita does not.

CONCLUSIONS: Gating pore currents arising from missense mutations at arginine residues in the voltage sensor domains of Na(V)1.4 are a common feature of HypoPP mutant channels and contribute to the attacks of paralysis.

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